Immunomodulatory therapy for chronic hepatitis B virus infection

Hepatitis B virus (HBV) is one of the most prevalent viral pathogens of man with around 350 million chronically infected patients. It has been postulated that in persistently infected individuals the HBV-specific immune response is too weak to eliminate HBV from all infected hepatocytes, but sufficiently strong to continuously destroy HBV-infected hepatocytes and to induce chronic inflammatory liver disease. The primary aim in the treatment of chronic hepatitis B is to induce sustained disease remission and prevent serious complications like liver failure and/or hepatocellular carcinoma. The recent emergence of drug-resistant HBV mutants and post-treatment relapse as a consequence of nucleoside analogue monotherapy emphasizes that the principal goal should be to stimulate a successful immune response. In this paper we will focus on the immune response to HBV and we will review reported data on immunotherapeutic strategies like immunomodulatory drugs (cytokines and Thymic derivates) and vaccine therapies using currently available recombinant anti-HBV vaccines, lipopeptide-based T cell vaccine and newly developed genetic vaccines.     

慢性乙型肝炎患者的个体化免疫调节治疗

慢性乙型肝炎(简称慢性乙肝)需要长期抗病毒治疗的概念已经形成共识.按照循证医学的原则和根据最新的研究成果,美国肝脏病研究协会( American Association for the Study of Liver Diseases,AASLD)和欧洲肝脏病协会(European Association for the Study of the Liver,EASL)分别发布了乙型肝炎实践指南[1-2],我国在2010年12月发布了修改的<慢性乙型肝炎防治指南>[3],这使得慢性乙肝的抗病毒治疗更加规范、科学、合理.     

Viral breakthrough during lamivudine therapy for chronic hepatitis B

The mainstay of therapy for patients with chronic hepatitis B is inhibition of the replicative cycle of hepatitis B virus (HBV) in hepatocytes. Antiviral agents have different potencies. The measurement of HBV DNA in serum can monitor the potency of these therapeutic agents. Viral breakthrough may occur during therapy, which is defined as an abrupt increase in serum HBV DNA levels after a period of persistent suppression. The accuracy of HBV DNA detection depends on the sensitivity of assays. The third-generation quantitative assays have a lower limit of detection in ranges similar to those of quantitative PCR reaching 2 log10 copies/ml. The sensitive assays also give insight into the pathophysiology of chronic hepatitis B. Monotherapy usually suppresses the viral replication inadequately. It only brings about a reduction of serum HBV DNA levels from 8 to 4 log10 copies/ml. In other words, HBV is not completely eliminated. Viral breakthrough occurs with noncompliance to therapy and, also, when drug-resistant mutants emerge. Mutations in the YMDD motif of HBV polymerase lead to resistance to antivirals, such as lamivudine and famciclovir. In clinical practice, the diagnosis and management of viral breakthroughs are problematic and controversial. Due to advances in therapy, more potent agents are available such as adefovir dipivoxil that seldom induce viral breakthroughs for up to 134 weeks of therapy. Potent antiviral agents also lead to the decline of cccDNA in hepatocytes. Combination therapies may further improve efficacy and avoid viral breakthroughs.     

慢性乙型肝炎患者的个体化免疫调节治疗

慢性乙型肝炎(简称"慢性乙肝")需要长期抗病毒治疗的概念已经形成共识.按照循证医学的原则和根据最新的研究成果,美国肝脏病研究协会( American Association for the Study of Liver Diseases,AASLD)和欧洲肝脏病协会(European Association for the Study of the Liver,EASL)分别发布了乙型肝炎实践指南[1-2],我国在2010年12月发布了修改的<慢性乙型肝炎防治指南>[3],这使得慢性乙肝的抗病毒治疗更加规范、科学、合理.     

慢性乙型肝炎患者的个体化免疫调节治疗

慢性乙型肝炎(简称"慢性乙肝")需要长期抗病毒治疗的概念已经形成共识.按照循证医学的原则和根据最新的研究成果,美国肝脏病研究协会( American Association for the Study of Liver Diseases,AASLD)和欧洲肝脏病协会(European Association for the Study of the Liver,EASL)分别发布了乙型肝炎实践指南[1-2],我国在2010年12月发布了修改的<慢性乙型肝炎防治指南>[3],这使得慢性乙肝的抗病毒治疗更加规范、科学、合理.     

Psychosis associated with interferon alfa therapy for chronic hepatitis B

OBJECTIVE: To report a case of persistent psychosis that developed during interferon alfa (IFN-alpha) therapy for chronic hepatitis B. CASE SUMMARY: A 26-year-old man who was diagnosed with active chronic hepatitis B began treatment with IFN-alpha. Five months after initiation of therapy, he developed acute psychosis with prominent persecutory delusions and auditory hallucinations. Despite discontinuation of IFN-alpha therapy and addition of antipsychotic drug treatment, only partial recovery from psychosis was observed after 4 months of hospitalization. DISCUSSION: Unlike many previously reported cases, this patient showed only partial recovery from psychosis, despite the discontinuation of IFN therapy. Except for receiving a relatively high dose of IFN-alpha (10 million units 3 times/wk), the patient did not have any previously proposed risk factors for developing psychiatric adverse effects. The Naranjo probability scale indicates a probable relationship between the acute psychosis and IFN therapy. CONCLUSIONS: Despite its rare occurrence, psychosis can emerge during IFN-alpha therapy. This adverse effect may persist for several months, even after appropriate medical management. IFN-alpha should be used with careful monitoring of patients' psychiatric status during all stages of therapy.     

Hepatitis B genotypes in chronic hepatitis B and lamivudine therapy

The influence of hepatitis B virus (HBV) genotypes on the natural history and the response to treatment of patients with chronic hepatitis B are of potential interest. Compared to the patients with HBV genotype C, those with genotype B were of a younger age and had a higher cumulative rate of hepatitis B e antigen (HBeAg) seroconversion during the initial 6 years of follow-up. The earlier HBeAg seroconversion in the patients with genotype B, however, did not provide them with a benefit in terms of a reduced risk of developing long-term complications. The response to lamivudine therapy was evaluated in 21 patients infected with HBV genotype B (all of subtype Ba) and 61 with genotype C. There were no differences in the virological response to lamivudine therapy, based on the reduction in median logarithmic HBV DNA titer as well as alanine aminotransferase (ALT) levels, normalization of ALT and the rate of HBeAg seroconversion between the patients with genotypes B and C. No differences were noted either, in the frequency of YMDD mutants at week 52 or the cumulative risk of HBV DNA breakthroughs with YMDD mutations during long-term lamivudine therapy (median 37.5 months). In conclusion, there is no influence of HBV genotypes on the development of long-term complications and lamivudine therapy in Hong Kong.     

Polymerase domain B mutation is associated with hepatitis relapse during long-term lamivudine therapy for chronic hepatitis B

Breakthrough hepatitis remains the major issue in long-term lamivudine therapy for chronic hepatitis B. However, the emergence of drug-resistant hepatitis B virus (HBV) is not always accompanied by a relapse of hepatitis. To elucidate factors predictive of breakthrough hepatitis, 53 patients with genotype C of HBV on long-term lamivudine therapy were analyzed. HBV reappeared during therapy in 19 patients with a cumulative incidence of 15% at 1 year, 34% at 2 years, and 60% at 3 years. Within this group, breakthrough hepatitis developed in 12 patients (63%). A polymerase gene domain B mutation (rt180M) emerged in 13 patients, and domain C mutations (rt204I, rt204V) were found in 19 patients. The rt180M mutation was associated with breakthrough hepatitis (p < 0.05) with a positive predictive value of 85% and a negative predictive value of 83%. Patients with the rt180M mutation had higher HBV-DNA levels during viral breakthrough compared to patients with rt180wt (p < 0.05). The mutational pattern of rt204 was not associated with breakthrough hepatitis. In conclusion, genotypic assays for the rt180M mutation after viral breakthrough may be useful in predicting the risk of breakthrough hepatitis and in deciding when to initiate alternative or additive nucleoside analogue therapy.     

慢性乙型肝炎抗病毒治疗的现状及进展

目前慢性乙型病毒性肝炎(chronic hepatitis B,CHB)的治疗包括聚乙二醇化干扰素(pegylated interferon,PEG-IFN)和核苷(酸)类似物[nucleos(t)ide analogs,NAs]。基于IFN的治疗时间是有限的,但只有20%~30%的患者实现血清学反应和持续的治疗后反应。NAs因其长期疗效有限导致治疗期延长,并且长期服用NAs可出现耐药突变体。很多研究结合PEG-IFN的免疫调节特性以及NAs的直接抗病毒活性,试图提高CHB患者的疗效。联合治疗虽然提高了患者的治疗中应答率,但并未改善治疗后反应。因此,目前迫切需要探索新的治疗策略。     

HBV相关中和抗体在慢性乙型肝炎抗病毒治疗中的研究进展

HBV感染不仅是一项重要的全球性公共卫生问题,也是我国正在面临的一项重要挑战。虽然现在已有针对HBV的疫苗并且其接种普及率也在逐年提高,但仍然有很多的乙型肝炎患者亟待治疗。中和抗体作为HIV一项重要的治疗方法同样在HBV的治疗研究领域被寄予厚望。目前针对HBV相关中和抗体的研究主要包括G12、Bc1.187、H017、...     

Lamivudine for chronic hepatitis B

Lamivudine (Epivir^®, GlaxoSmithKline) was approved by the US Food and Drug Administration for the treatment of adult patients with chronic hepatitis B in 1998, and has since been shown to be of benefit to selected patients with chronic hepatitis B. Drug resistance is the main issue encountered during therapy, with lamivudine resistant mutants emerging at a rate of approximately 15 to 30% per year of therapy. These mutants are associated with relapse of hepatitis, and occasionally hepatic decompensation. Despite this, therapeutic indications and guidelines for lamivudine therapy have now been drawn up, which indicate that lamivudine will be the first line therapy for hepatitis B e antigen-positive chronic hepatitis B patients, although its role in hepatitis B e antigen-negative patients remains controversial.     

Lamivudine for chronic hepatitis B

Lamivudine (Epivir, GlaxoSmithKline) was approved by the US Food and Drug Administration for the treatment of adult patients with chronic hepatitis B in 1998, and has since been shown to be of benefit to selected patients with chronic hepatitis B. Drug resistance is the main issue encountered during therapy, with lamivudine resistant mutants emerging at a rate of approximately 15 to 30% per year of therapy. These mutants are associated with relapse of hepatitis, and occasionally hepatic decompensation. Despite this, therapeutic indications and guidelines for lamivudine therapy have now been drawn up, which indicate that lamivudine will be the first line therapy for hepatitis B e antigen-positive chronic hepatitis B patients, although its role in hepatitis B e antigen-negative patients remains controversial.     

Continued lamivudine therapy in patients with chronic hepatitis B

From September 1995 through April 2002, 286 patients with chronic hepatitis B were started on lamivudine at the Toranomon Hospital in Tokyo, Japan, and most of them continued with it. At present, 16 patients received lamivudine for 5 years, 7 of whom for 7 years or longer. YMDD mutants increased gradually and developed in 69% of them during the 7 years on lamivudine. Biochemical and virological responses were achieved in 9 of the 16 patients (56%) at 5 years, and in 4 of the 7 patients (57%) at 7 years. Histological assessments were performed at 3 years in the 16 patients and further at 4 and 7 years in the 7 patients. Necroinflammatory changes improved remarkably with a decrease in the total histological activity score from 11.3 +/- 3.0 to 4.1 +/- 1.7 (p < 0.0001) at 3 years in the 16 patients. Histological improvements continued in 4 of the 7 patients (57%) at 7 years on lamivudine, while the pathology was unchanged in 2 patients (29%) and aggravated in the remaining 1 patient (14%). Severe acute exacerbation of hepatitis developed in 1 patient, who received additional interferon-alpha therapy to cope with it. Based on my experience, the continuation of lamivudine in patients with chronic hepatitis B benefits approximately two thirds of them with persistent virological and biochemical responses accompanied by histological improvements. Breakthrough hepatitis induced by YMDD mutants along the way in a small number of patients needs to be diagnosed promptly by regular monitoring for transaminases and, if it develops, it can be treated with interferon or other antiviral agents.     

Discontinuation of antiviral therapy in chronic hepatitis B patients

Nucleos(t)ide analogs (NUC) are the first-line therapy for patients with chronic hepatitis B (CHB) recommended by most current guidelines. NUC therapy decreases progression of liver disease, reduces the risk of liver-related complications, and improves the quality of life of patients with CHB. Although indefinite or long-term NUC therapy is usually recommended, this strategy raises several concerns, such as side-effects, adherence, costs, and patient willingness to stop therapy. Recent data showed the feasibility, efficacy, and safety of stopping antiviral therapy in carefully selected CHB patients, leading to its incorporation in international guidelines. Patients who discontinue NUC have a higher likelihood of hepatitis B surface antigen (HBsAg) loss compared to patients who continue on therapy. Recommendations pertaining endpoints allowing safety discontinuation of NUC therapy differ among international guidelines. For hepatitis B e antigen (HBeAg)-positive patients, durable HBeAg seroconversion is considered an acceptable treatment endpoint. For HBeAg-negative patients, some guidelines propose undetectability hepatitis B virus DNA for at least 2 or 3 years, while others consider HBsAg loss as the only acceptable endpoint. CHB patients who stop therapy should remain under strict clinical and laboratorial follow-up protocols to detect and manage relapses in a timely manner. No reliable predictor of relapse has been consistently identified to date, although quantitative HBsAg has been increasingly studied as a reliable biomarker to predict safe NUC discontinuation.